tbuckley/cabot-search huggingface dataset:
The experience of the COMRE group (REctal COMmittee): can magnetic resonance imaging and endosonography really help the clinical pathway after NCRT in rectal cancer?
Authors: Stefano Scabini, Chiara Romana, Marina Sartini, Ali Attieh, Ciro Marrone, Maria L. Cristina, Maria C. Parodi
Journal: International Journal of Surgery (2023)

MRI and rectal endosonography (EUS) are routinely used for preoperative tumor staging and assessment of response to therapy in patients with rectal cancer. This study aimed to evaluate the accuracy of the two techniques in predicting the pathological response compared to the resected specimen and the agreement between MRI and EUS and to define the factors that could affect the ability of EUS and MRI to predict pathological responses.This study included 151 adult patients with middle or low rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy, followed by curative intent elective surgery in the Oncologic Surgical Unit of a hospital in the north of Italy between January 2010 and November 2020. All patients underwent MRI and rectal EUS.The accuracy of EUS to evaluate the T stage was 67.48%, and for the N stage was 75.61%; the accuracy of MRI to evaluate the T stage was 75.97%, and that for the N stage was 51.94%. The agreement in detecting the T stage between EUS and MRI was 65.14% with a Cohen's kappa of 0.4070 and that for the evaluation of the lymph nodes between EUS and MRI was 47.71% with a Cohen's kappa of 0.2680. Risk factors that affect the ability of each method to predict pathological response were also investigated using logistic regression.EUS and MRI are accurate tools for rectal cancer staging. However, after Radiotherapy - Chemotherapy RT-CT, neither method is reliable for establishing the T stage. EUS seems significantly better than MRI for assessing the N stage. Both methods can be used as complementary tools in the preoperative assessment and management of rectal cancer, but their role in the assessment of residual rectal tumors cannot predict the complete clinical response.
The risk of venous thromboembolism in atopic dermatitis: a matched cohort analysis in UK primary care
Authors: Richard B Warren, Victoria Basey, Anita Lynam, Charlotte Curtis, Michael R Ardern-Jones
Journal: British Journal of Dermatology (2023)

Atopic dermatitis (AD) is a common chronic inflammatory skin condition. While other chronic inflammatory conditions are associated with increased risk of venous thromboembolism (VTE), associations between AD and VTE have not been established.We examined whether AD is associated with an increased risk of VTE in a population-based study.Electronic health records were extracted from UK general practices contributing to the Optimum Patient Care Research Database (1 January 2010 to 1 January 2020). All adults with AD were identified (n = 150 975) and age- and sex-matched with unaffected controls (n = 603 770). The risk of VTE, consisting of pulmonary embolism (PE) or deep-vein thrombosis (DVT), was compared in people with AD vs. controls using Cox proportional hazard models. PE and DVT were examined separately as secondary outcomes.We identified 150 975 adults with active AD and matched them with 603 770 unaffected controls. During the study, 2576 of those with active AD and 7563 of the matched controls developed VTE. Individuals with AD had a higher risk of VTE than controls [adjusted hazard ratio (aHR) 1.17, 95% confidence interval (CI) 1.12-1.22]. When assessing VTE components, AD was associated with a higher risk of DVT (aHR 1.30, 95% CI 1.23-1.37) but not PE (aHR 0.94, 95% CI 0.87-1.02). The VTE risk was greater in older people with AD (≥ 65 years: aHR 1.22, 95% CI 1.15-1.29; 45-65 years: aHR 1.15, 95% CI 1.05-1.26; < 45 years: aHR 1.07, 95% CI 0.97-1.19) and those with obesity [body mass index (BMI) ≥ 30: aHR 1.25, 95% CI 1.12-1.39; BMI < 30: aHR 1.08, 95% CI 1.01-1.15). Risk was broadly consistent across mild, moderate or severe AD.AD is associated with a small increase in risk of VTE and DVT, with no increase in risk of PE. The magnitude of this risk increase is modest in younger people, and those without obesity.
P24 Emollient use and effects on cutaneous allergen reactions: a preliminary study
Authors: Oludolapo Sherifat Katibi, Paul Andrew, Anna  Poyner, Abigail Pinnock, Kirsty Brown, Rob  Byers, Michael Cork, Simon Danby
Journal: British Journal of Dermatology (2023)

Abstract Recently, there has been some evidence of an increased incidence of food allergy in infants regularly applying some types of emollients. Considering that emollient vehicles can modify the delivery of ‘actives’ into the skin, it is important to examine their effects on epicutaneous sensitization to environmental allergens. The aim was to determine the effects of regular emollient use on cutaneous reactions to house dust mite allergen. An observer-blind within-participant multilateral controlled interventional study in 40 adults with confirmed house dust mite allergy was carried out. Participants underwent 4 weeks of treatment with olive oil, coconut oil and a basic emollient cream (no added moisturizers) applied to three different areas of both forearms with a fourth area left as a no-treatment control (NTC). At the end of treatment, skin barrier integrity was assessed by performing transepidermal water loss (TEWL) measurements in conjunction with tape-stripping. At adjacent locations, atopy patch tests (APTs) using house dust mite allergen were performed. This interim analysis includes data from the first 16 participants. Skin barrier integrity was reduced by all three treatments relative to NTC as indicated by elevated TEWL [mean (SD) olive oil 35.10 (15.17), coconut oil 36.56 (17.17) and emollient cream 39.18 (20.91) vs. NTC 28.76 (13.06) g m–2 h–1; P &amp;lt; 0.05]. Pretreatment of the skin had a significant effect on APT reactions (P = 0.0401, graded from 0 to 4). The strongest reactions were seen following pretreatment with emollient cream [2.31 (1.12)], olive oil [2.22 (0.91)] and coconut oil [1.94 (0.91)] vs. NTC [1.50 (0.80)]. These preliminary results suggest that some commonly used emollients decrease skin barrier integrity and increase the severity of reactions to house dust mite allergens. This implies that regular use of emollients that damage the skin may directly affect allergy development arising from epicutaneous sensitization. Some sophisticated emollients (with moisturizers) have been shown to improve skin barrier function. Clinical trials are therefore needed to determine if they impart protection against epicutaneous sensitization.
P29 Manuka honey downregulates IL-4-induced CCL26 via activation of the aryl hydrocarbon receptor
Authors: Abdullah A Alangari, Matin Dokht Ashoori, Wisam Alwan, Brigitta Stockinger, Jonathan N   Barker, Emma Wincent, Paola  Di Meglio
Journal: British Journal of Dermatology (2023)

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates skin homeostasis. AHR activation by physiological ligands (e.g. indoles originated from host or microbial metabolism of tryptophan) leads to the expression of cytochrome P450 (CYP) enzymes, such as CYP1A1 and has anti-inflammatory effects in animal models and clinical samples of psoriasis and atopic dermatitis. Manuka honey (MH) is a complex nutritional material with antimicrobial, antioxidant and anti-inflammatory activity. We have previously shown that MH downregulates interleukin (IL)-4-induced CCL26 expression in immortalized keratinocytes. Recent studies suggest that MH contains potential AhR ligands, including indoles. Thus, we hypothesize that its anti-inflammatory effect may be mediated, at least partially, via AhR activation. Here, we treated HaCaT keratinocytes, either stably transfected with an empty vector (EV-HaCaT) or in which AhR had been stably silenced (AhR-silenced HaCaT), or primary normal human epithelial keratinocytes (NHEK) with 2% MH for 24 h and measured gene expression by reverse transcriptase quantitative polymerase chain reaction. We detected a 15.4-fold upregulation of CYP1A1 in EV-HaCaTs, which was significantly reduced (P ≤ 0.001) in AhR-silenced cells. Pretreatment with the AhR antagonist CH223191 significantly (P ≤ 0.0001) abrogated this effect. Similar findings were observed in NHEKs. In vivo epicutaneous treatment of Cyp1a1Cre × R26ReYFP reporter mice with pure MH significantly (P &amp;lt; 0.0001) induced CYP1A1 expression compared with Vaseline. Treatment of HaCaT with 2% MH significantly decreased (P &amp;lt; 0.0001) baseline CYP1A1 enzymatic activity at 3 and 6 h but increased it after 12 h, suggesting that MH may activate the AhR through both direct and indirect means. Importantly, MH downregulation of IL-4-induced CCL26 mRNA and protein was abrogated in AhR-silenced HaCaTs and by pretreatment with CH223191. Finally, MH significantly (P &amp;lt; 0.0001) upregulated filaggrin (FLG) expression in NHEKs in an AhR-dependent manner. In conclusion, MH activates AhR, both in vitro and in vivo, thereby providing a mechanism of its IL-4-induced CCL26 downregulation and upregulation of FLG expression. Taken together, our data show that the AhR-activating properties of MH could have broader clinical implications in a range of skin inflammatory conditions.
Weekday-dependent long-term outcomes in gastrointestinal cancer surgery: a German population-based retrospective cohort study
Authors: Christopher F. Maier, Caroline Schölch, Lei Zhu, Martial M. Nzomo, Helmut L’hoest, Ursula Marschall, Christoph Reißfelder, Sebastian Schölch
Journal: International Journal of Surgery (2023)

Background: For most solid cancers, surgery represents the mainstay of curative treatment. Several studies investigating the effects of the weekday of surgery (WOS) on patient outcomes have yielded conflicting results. Barmer, the second-largest health insurance company in Germany, serves roughly 10% of the German population. We have used the Barmer database to evaluate how the weekday on which the surgery is performed influences long-term oncologic outcomes. Methods: For this retrospective cohort study, the Barmer database was used to investigate the effect of the WOS (Monday–Friday) on outcomes following oncological resections of the colorectum (n=49,003), liver (n=1,302), stomach (n=5027), esophagus (n=1126), and pancreas (n=6,097). In total, 62,555 cases from 2008 to 2018 were included in the analysis. The endpoints were overall survival (OS), postoperative complications, and necessity for therapeutic interventions or re-operations. We furthermore examined whether the annual caseload or certification as a cancer center influenced the weekday effect. Results: We observed a significantly impaired OS for patients receiving gastric or colorectal resections on a Monday. Colorectal surgery performed on Mondays was associated with more postoperative complications and higher probability of re-operations. The annual caseload or a certification as a colorectal cancer center had no bearing on the observed weekday effect. There is evidence that hospitals schedule older patients with more comorbidities earlier in the week, possibly explaining these findings. Conclusion: This is the first study investigating the influence of the WOS on long-term survival in Germany. Our findings indicate that, in the German healthcare system, patients undergoing colorectal cancer surgery on Mondays have more postoperative complications and, therefore, require significantly more re-operations, ultimately lowering OS. This surprising finding appears to reflect an attempt to schedule patients with higher postoperative risk earlier in the week as well as semi-elective patients admitted on weekends scheduled for surgery on the next Monday.
P17 A signature of IL-36 activation in systemic lupus erythematosus skin
Authors: Emma J Sumner, Daniel McCluskey, Satveer K   Mahil, Myles Lewis, Francesca  Capon
Journal: British Journal of Dermatology (2023)

Abstract Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with heterogeneous presentation. Joint and kidney disease represent the largest cause of morbidity, and visually distinctive skin complications are often present. While it has long been established that organ damage is caused by autoantibodies forming large immune complexes in the affected tissues, a detailed understanding of disease processes is still lacking. Here, we propose that interleukin (IL)-36 cytokines, which drive cutaneous and systemic symptoms in psoriasis, are also implicated in the pathogenesis of SLE. Given that the IL-36 receptor is prominently expressed in keratinocytes, we investigated this hypothesis in skin. We first carried out a systematic review of SLE single-cell RNA sequencing studies, identifying two data sets (∼50 000 cells in total) generated from patient skin biopsies. We processed both data sets with the same standardized pipeline, using the Seurat package. This identified 10 distinct cell clusters, replicating the cell types described in the original studies and identifying the main cell populations observed in human skin. Subsequent gene expression analysis confirmed that, in both data sets, the expression of IL36G and IL1RL2 (the genes encoding IL-36γ and its receptor) was highest in keratinocytes. Interestingly, subclustering showed that this signal was driven by the expression of IL36G in supraspinous keratinocytes and of IL1RL2 in proliferating keratinocytes. In the first data set, the expression of IL36G and IL1RL2 was readily detectable in lesional keratinocytes but virtually nonexistent in their nonlesional counterparts. A comparison of lesional and nonlesional keratinocytes also identified 297 differentially expressed genes (DEGs; log2 fold change &amp;gt; 1.2, false discovery rate &amp;lt; 0.05) in the first study and 234 in the second. To further explore these findings, we compared the above DEG with a set of 182 genes (previously defined by our group) that are upregulated in IL-36-stimulated keratinocytes. This demonstrated a significant over-representation of the IL-36 signature genes among the DEGs observed in lesional SLE keratinocytes (P &amp;lt; 0.005 in both data sets). These observations indicate that IL-36 is likely to contribute to skin inflammation in SLE, warranting further studies of this cytokine in organs affected by the disease.
P23 Inducible E-cadherin ablation drives malignant progression in HK1.ras.fos.PTENflx/flx carcinogenesis and induces conversion of HK1.fos.PTENflx/flx keratoacanthoma
Authors: Rema Zaweia, Abdullah Alyamani, Carol  McMenemy, Jean Quinn, David  Greenhalgh
Journal: British Journal of Dermatology (2023)

Abstract Inducible ablation of E-cadherin expression has been investigated in mouse skin carcinogenesis driven by Ras and Fos activation (HK1.ras; HK1.fos), and conditional (cre/lox) PTEN knockout exclusively in the epidermis. Previously, analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours showed E-cadherin expression became reduced at the invasive front of well-differentiated squamous cell carcinomas (wdSCCs) following p53 loss, and where retention of p21 minimized Akt activation and further progression. To validate stage-specific causality of E-cadherin loss, RU486-inducible conditional E-cadherin knockout was introduced into HK1.ras/fos/Δ5PTENflx/flx genotypes employing the cre/LoxP system (K14cre-ΔE-cadflx/flx). Initial observations in RU486-treated compound HK1.ras/fos/ΔPTENflx/flx-ΔE-cadflx/flx mice found that E-cadherin ablation appeared to accelerate malignant conversion, again associated with p53 loss; however, the main effect was on malignant progression and invasion, as wdSCCs displayed rapid progression to aggressive SCCs. Malignant progression also implicated β-catenin activation, finding increased nuclear expression, alongside loss of membranous expression, in the invasive basal layer keratinocytes, together with loss of p21 and increased p-Akt1 activity. In addition, preliminary data for E-cadherin loss in HK1.fos/Δ5PTEN keratoacanthoma aetiology now showed malignant conversion to invasive wdSCC, again associated with increased β-catenin activation. These wdSCCs may have retained a degree of correct adhesion signalling, as basal layer HK1.fos/Δ5PTEN-ΔE-cadflx/flx keratinocytes exhibited both membranous and nuclear p-β-catenin expression; hence, in the absence of Ras, progression stalled at wdSCC. Collectively, these data show that, in some contexts (hyperplasia/papillomas), E-cadherin loss can be tolerated via increased differentiation, while in carcinogenesis, following overt tumour appearance, conditional ablation of E-cadherin drives invasion and malignant progression, consistent with roles in cell–cell adhesion and deregulated signalling to β-catenin.
P05 Inducible MDM2 ablation increases p53 expression to block papillomatogenesis in HK1.ras transgenic mice
Authors: Ana Gutierrez Crispini, Aleksandra Slosarska, David Greenhalgh
Journal: British Journal of Dermatology (2023)

Abstract Previously, p53 loss was a consistent theme in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of phosphatase and tensin homolog (PTEN)-mediated Akt regulation (K14.creP/Δ5PTENflx), leading to well-differentiated squamous cell carcinoma. Given that MDM2 is a ubiquitin ligase that targets p53 for degradation, the potential efficacy of MDM2 functional knockout to protect p53 levels and thus inhibit tumour formation was investigated. Initial experiments investigated the inhibition of benign papilloma formation in HK1.ras mice as analysis of endogenous MDM2 status showed that activated p-MDM2166 activity was confined to suprabasal layers, resulting in strong nuclear p53 expression in basal layers that inhibited conversion. Yet, earlier hyperplasia expressed only sporadic p53/MDM2, suggesting that should MDM2 activity be inhibited, increased p53 in hyperplasia may inhibit papilloma formation. Therefore, loss of MDM2-mediated p53 degradation was investigated via inducible ablation of MDM2 exons 5 and 6, which bind p53 and chaperone for ubiquitination, employing K14-driven Cre/lox-P and treatment with topical RU486 (K14cre-Δ5/6MDM2flx/flx). In control, RU486-treated K14cre-Δ5/6MDM2flx/flx littermates, surprisingly few effects were observed, as normal epidermis expressed only sporadic p53/MDM2 as keratinocytes divided. Similarly, early HK1.ras hyperplasia displayed sporadic p53/MDM2 coexpression, suggesting an epidermis was relatively tolerant of Ras-mediated proliferation, where p53 overexpression risks problems of barrier maintenance due to excess apoptosis. With time, HK1.ras papillomas increased nuclear basal layer p53; p-MDM2166 also increased but remained suprabasal – alongside p-Akt1473 – possibly geared to maintain barrier functions from potential p53-mediated apoptosis. Conversely, in RU486-treated HK1.ras-Δ5/6MDM2flx/flx littermates, while hyperplasia histotype appeared unaffected, expression analysis found strong, elevated p53 expression in all compartments, consistent with loss of MDM2 inhibition. Moreover, this level of basal layer p53 in early hyperplasia apparently blocked papilloma formation and fed back to inhibit p-Akt1, whereas heterozygous MDM2 HK1.ras-Δ5/6MDM2flx/wt littermates exhibited a papillomatogenesis identical to wild-type HK1.ras littermates, with suprabasal p-MDM2166 and p-Akt1473. These findings suggest that MDM2 inhibition can inhibit benign tumour formation via maintaining p53 levels; however, with time (&amp;gt; 20 weeks), small papillomas did appear, showing that this inhibition can be circumvented.
O15 Using CRISPR-Cas9 to annotate the TYK2 pathway in psoriasis
Authors: Sarah Elyoussfi, Shraddha S Rane, Stephen  Eyre, Richard B Warren
Journal: British Journal of Dermatology (2023)

Abstract Genome-wide association studies (GWAS) have discovered genetic signals associated with psoriasis. This study is the first to validate functionally the psoriasis-associated single nucleotide polymorphism (SNP) rs892085 on TYK2 expression using clustered regularly interspaced short-palindromic repeat Cas9 endonuclease (CRISPR-Cas9) technologies in Jurkat T-lymphoblast cells. Our in-house capture Hi-C data revealed long-range chromatin interactions between specific SNP sets and TYK2. An independent noncoding genetic association with psoriasis was identified about 400 kb upstream of TYK2: rs892085 at 19p13.2. This is a psoriasis-associated risk SNP (P = 3.0 × 10–17). To characterize fully the physical connection, CRISPR-Cas9 genome editing was conducted in T-cell-like Jurkat T-lymphoblast cell lines. We used the CRISPR activator (CRISPR/dCas9-VP64) and CRISPR interference (CRISPR/dCas9-KRAB) systems to alter the transcriptional activity of regions to which they are targeted. We performed reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) to identify differential gene expression between modified and control cells. RT-qPCR revealed consistent alteration of TYK2 expression upon inhibition and activation of rs892085. This supports previous observations, where this regulatory region harbouring GWAS-implicated variation operates through direct long-distance contact. To associate genes with disease, the closest or most biological relevant gene is often assigned to a GWAS variant. We have shown that this is not always reliable, with DNA regions looping over large distances to control genes. This provides the first functional validation of the psoriasis-associated SNP rs892085. GWAS have linked TYK2 to psoriasis susceptibility and TYK2 is a recognized drug target with one therapy, deucravacitinib, already approved by the US Food and Drugs Administration. This work demonstrates how risk alleles may work to dysregulate TYK2 signalling in disease. Ultimately, genetic risk scores may be generated to predict how a patient may respond to tyrosine kinase 2 (TYK2) therapy. Functional annotation of loci that perturb the TYK2 pathway will be the key to optimizing TYK2 therapy for the right person at the right time.